EP3139938B1 - Matrix-metalloproteinasehemmender extrakt und verwendungsverfahren dafür - Google Patents

Matrix-metalloproteinasehemmender extrakt und verwendungsverfahren dafür Download PDF

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EP3139938B1
EP3139938B1 EP15789343.9A EP15789343A EP3139938B1 EP 3139938 B1 EP3139938 B1 EP 3139938B1 EP 15789343 A EP15789343 A EP 15789343A EP 3139938 B1 EP3139938 B1 EP 3139938B1
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Prior art keywords
honey
extract
ethanol
mmp
skin care
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French (fr)
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EP3139938A4 (de
EP3139938A1 (de
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Gregor Aaron STEINHORN
Sigrid VORWERK
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Comvita Ltd
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Comvita Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/98—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin
    • A61K8/987—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution of animal origin of species other than mammals or birds
    • A61K8/988—Honey; Royal jelly, Propolis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
    • A61K35/64—Insects, e.g. bees, wasps or fleas
    • A61K35/644—Beeswax; Propolis; Royal jelly; Honey
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/805—Corresponding aspects not provided for by any of codes A61K2800/81 - A61K2800/95

Definitions

  • MMP matrix-metalloproteinase
  • Honey is a well known active ingredient in many products including use in culinary applications, topical medical treatments including incorporation into existing cosmetic skin care formulations.
  • Cosmetic skin care formulations often may not have sufficient honey included to confer any activity or if present, or the type of honey chosen only provides a low level if any of MMP inhibition. This is because honey at higher concentrations leads to formulation issues such as stickiness and high viscosity form the honey plus the inventors have found that only certain honey types confer MMP inhibition.
  • MMP Matrix-metalloproteinases
  • UV ultra-violet radiation
  • MMP inhibitors are useful ingredients in anti-aging skin care formulations as they reduce photo-aging of the skin caused by collagen degradation. Natural MMP inhibitors have recently gained favour in the market.
  • Manuka honey can have MMP inhibition effects.
  • Manuka honey is derived from the plant species Leptospermum scoparium and contains a wide range of phenolic and flavonoid compounds some of which have been identified and others remain as yet unknown. The exact activities of the various phenolics and flavonoids is still an area of rich research with many new compounds being identified and the activities elucidated.
  • Manuka honey is a particularly well known honey for it's non-peroxide effects thanks in part to acceptance into topical medical applications and in particular, the anti-bacterial effects of methyl glyoxal (MGO) in this honey.
  • MGO methyl glyoxal
  • Leptospermum genus honeys also have similar anti-bacterial effects linked with MGO such as Leptospermum sub pneumonia and Leptospermum polygalifolium.
  • MGO Leptospermum submur and Leptospermum polygalifolium.
  • further honeys derived from Kunzea and Knightia genus such as kanuka ( Kunzea ericoides ) and rewarewa ( Knightia excelsa ) honeys also have high levels of phenolic and flavonoid concentrations. These honeys do not contain MGO but nevertheless show promise in having other forms of activity in vivo.
  • the phenolic component of honey appears to be the main component responsible for MMP inhibitory effects. Whilst the exact phenolic compounds conferring the activity are not known, the inventors have identified that phenolic extracts have this activity.
  • Methylsyringate (although itself not active) is a basic building block of many phenolic compounds. It can be measured easily (for example via HPLC) and is found in phenolic rich honeys. Methyl syringate can be found in existing commercialised skin care formulations in concentrations ranging from 8 to 40 ⁇ g/mL and by inference, a range of methyl syringate related phenolic compounds are also present in these products. In any case, the presence and extent of MMP inhibition effects appear to correlate to the concentration of methyl syringate in the extract.
  • honey does present a significant challenge when formulating skin care products.
  • the formulator wants to maximise the concentration of honey in the formulation in order to maximise the MMP inhibition activity.
  • the sugars in the honey can prove troublesome in skin care formulations. The sugars can cause an unpleasant, sticky skin feel and there can be issues with skin absorbtion. This therefore limits the concentration of honey possible and hence limits the activity of the final product.
  • MMP inhibitory extract Described herein is an MMP inhibitory extract and methods of use thereof. More specifically, an extract derived from honey is described as well as uses of this extract in the inhibition of matrix-metalloproteinase (MMP) activity and related skin care products.
  • MMP matrix-metalloproteinase
  • the extract allows for the inclusion of much greater concentrations of phenolics and hence much higher MMP inhibitory effects whilst avoiding formulating issues inherent to use of untreated honey.
  • a cosmetic skin care product comprising a therapeutically effective amount of a honey extract, the honey extract having a phenolic compounds to saccharides ratio of at least 5 times greater than the raw honey from which the extract is derived and including a mixture of at least ethanol, water and one or more MMP inhibitory phenolic compounds.
  • a therapeutically effective amount of honey extract in the manufacture of a cosmetic skin care product to inhibit MMP activity on or in the skin of a subject to whom the cosmetic product is applied, wherein the cosmetic skin care product contains a honey extract, the honey extract having a phenolic compounds to saccharides ratio of at least 5 times greater than the raw honey from which the extract is derived and including a mixture of at least ethanol, water and one or more MMP inhibitory phenolic compounds.
  • a method of treatment of a cosmetic skin condition by topical application of a cosmetic skin care product to the skin of a subject wherein the cosmetic skin care product acts to inhibit skin MMP activity and wherein the cosmetic skin care product contains a therapeutically effective amount of a honey extract, the honey extract having a phenolic compounds to saccharides ratio of at least 5 times greater than the raw honey from which the extract is derived and including a mixture of at least ethanol, water and one or more MMP inhibitory phenolic compounds.
  • a method of producing an MMP inhibiting honey extract including the steps of:
  • the above extract, product, uses and methods allow the ability to include a far greater concentration of MMP inhibiting compounds in cosmetic skin care products than is possible with pure honey.
  • pure honey when used in skin care products confers unwanted characteristics to the product.
  • the extraction product and method also have some additional advantages namely, stabilisation and preservation of the phenolics and transdermal enhancing features. The result is an enhanced value product with better efficacy in combination with improved stability, handling and use properties.
  • an MMP inhibitory extract and methods of use thereof are described. More specifically, an extract derived from honey is described as well as uses of this extract in the inhibition of matrix-metalloproteinase (MMP) activity and related skin care products.
  • MMP matrix-metalloproteinase
  • the extract allows for the inclusion of much greater concentrations of phenolics and hence much higher MMP inhibitory effects whilst avoiding formulating issues inherent to use of untreated honey.
  • the term 'about' or 'approximately' and grammatical variations thereof mean a quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% to a reference quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length.
  • substantially' or grammatical variations thereof refers to at least about 50%, for example 75%, 85%, 95% or 98%.
  • the term 'skin care product' or grammatical variations thereof refers to topically applied formulations for cosmetic use.
  • compositions that may be applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance of wrinkles.
  • 'therapeutically effective amount' or grammatical variations thereof, with reference to an amount or dosage of a composition described herein, refers to an amount of a composition that is sufficient to cause a cosmetic effect.
  • 'honey' or grammatical variations thereof refers to a sweet and viscous fluid produced by honeybees and other insects from the nectar of flowers.
  • 'pure honey' or 'unextracted honey' or 'raw honey' or grammatical variations thereof as used herein refer to a honey that has been produced by bees. Normal processing steps may have occurred such as water removal or reduction, filtration of the honey by up to 50 micron and/or sterilisation, for example via irradiation.
  • honey produced from nectar at least about 50%, or 75%, or 85%, or 95% or 98%, of which is derived from the species noted.
  • the phenolic compounds referred to herein may be simple phenols or polyphenolics.
  • MMP inhibition refers to compounds that inhibit matrix metalloproteinase (MMP) activity in vivo. MMP activity may be completely stopped (full inhibition) or reduced to at least some extent dependent on the concentration of MMP inhibitors present as well as the relative inhibitory strength of the inhibitory compounds present.
  • a cosmetic skin care product comprising a therapeutically effective amount of a honey extract, the honey extract having a phenolic compounds to saccharides ratio of at least 5 times greater than the raw honey from which the extract is derived and including a mixture of at least ethanol, water and one or more MMP inhibitory phenolic compounds.
  • the extract above may have a phenolic compounds to saccharides ratio of approximately 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, 20, or more times greater than the raw honey form which the extract is derived.
  • the extract may have a phenolic compound to saccharides ratio approximately 10-20 times greater than the raw honey.
  • the extract may have a phenolic compound to saccharides ratio approximately 15 times greater than the raw honey.
  • the extract above may have a concentration of methyl syringate approximately 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20 times higher than the concentration of methyl syringate in the raw honey.
  • the extract may have a concentration approximately 10-20 times more methyl syringate than the raw honey.
  • the extract may have a concentration approximately 15 times more methyl syringate than the raw honey. It should be appreciated that methyl syringate is not an MMP inhibitory compound itself however; this compound is easy to measure and provides a repeatable and reliable measure of general MMP inhibitory phenolic concentration.
  • methyl syringate can provide a useful method of measuring MMP inhibition. Measurement may be completed via various known methods including, for example, via high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the extract may contain approximately 200, or 300, or 400, or 500, or 600, or 700, or 800, or 900, or 1000 ⁇ g/mL of methyl syringate. In one embodiment, the extract may contain 200 to 1000 ⁇ g/mL of methyl syringate. As may be appreciated, this level of methyl syringate is greatly increased over that typically measured in honey or skin care products. By way of illustration one commercially available skin care product includes only 8 to 40 ⁇ g/mL of methyl syringate (and by inference similarly low other phenolic concentrations) compared to the extract noted above.
  • methyl syringate is a simple phenolic compound form which many other phenolic compounds are derived.
  • the exact phenolic compound(s) responsible for the observed MMP inhibition are not specifically known however, by way of illustration, honey contains many phenolics some of which are demonstrated in the table below: Apigenin Caffeic acid Chlorogenic acid Chrysin Coumaric acid Ellagic acid Ferulic acid Galangin Gallic acid Kaempferol Myricetin Luteolin Pinocembrin Quercetin Syringic acid
  • the actual active phenolic compound may be any one of these or may be a synergy of these or even other compounds.
  • the MMP's inhibited may be MMP-1 (collagenase-1), MMP-2 (gelatinase-A) and MMP-9 (gelatinase-B).
  • the degree of inhibition as measured based on 0.5% phenolics in the honey extract may be at least 10%. It should be appreciated that the measured degree of inhibition in the cosmetic skin care product may vary depending on the concentration of phenolics in the product and their floral origin and this figure is provided by way of illustration only.
  • the extract prior to formulation in the skin care product may contain approximately 10, or 15, or 20, or 25, or 30, or 35, or 40, or 45, or 50, or 55, or 60, or 65, or 70, or 75, or 80% ethanol.
  • the extract may contain approximately 50 to 70% ethanol. It should be appreciated that this amount is provided by way of illustration however, the actual amount of ethanol may vary significantly depending on the amount of ethanol separation completed (e.g. via evaporation or distillation) and various other parameters such as the desired amount of ethanol wanted in the extract to assist further formulation work.
  • retaining ethanol in the extract may be important and beneficial to aid with (a) phenolic stability during storage before formulation; (b) to act as a preservative and avoid microbial growth and (c) ethanol assists with transdermal penetration of the phenolics when formulated.
  • the phenolic compounds extracted are understood at least in part to be immiscible in water.
  • the presence of ethanol in the extract means that the phenolic compounds remain in solution and avoids precipitation issues and hence instability and separation.
  • ethanol acts as a preservative preventing or at least limiting the growth of microbes in the solution.
  • Both the stabilisation and preservation characteristics of ethanol in this application mean that the extract can be stored for a considerable period of time prior to formulation as a skin care product.
  • the last advantage of ethanol is that phenolics in the ethanol will be more readily absorbed into the skin since ethanol is a transdermal enhancer. Having the phenolics in a ready state for application makes formulation easier and avoids or at least minimises the need to add additional transdermal agents. From a marketing and commercial perspective, ethanol may also be also be advantageous as a solvent since ethanol can be manufactured or obtained from natural processing methods and is well known and used in industry.
  • the extract prior to formulation in the skin care product may contain approximately 0.1, or 0.5, or 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18% water. In one embodiment the extract may contain approximately 5 to 15% water. In one embodiment, the extract may contain 8 to 12% water. As may be appreciated, honey inherently contains up to 18% water naturally and the water in the extract may be that retrieved from the honey itself and not added by any other means.
  • the skin care product may contain approximately 0.1, or 0.2, or 0.3, or 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20% (w/w) of extract.
  • the skin care product may contain approximately 1 to 5% extract.
  • approximately 2% extract in a skin care product gives an MMP inhibitory effect equivalent to that of a 30% pure honey concentration. This level of honey in a skin care product would be entirely unmanageable with many issues such as separation, stability, odour, a high viscosity and a high stickiness. All of these factors effectively render such as product unmarketable.
  • the skin care product noted above has none of the negative effects of pure honey and can be easily formulated (at 2% or even higher or lower as desired).
  • the cosmetic skin care product as described above may be formulated for topical administration as creams, gels, ointments, bars, lotions, or liquids.
  • Specific product types include cleaners and toners, exfoliators and masks, moisturisers and lotions, and serums.
  • honey from which the extract is derived are those naturally rich in phenolic compounds, namely derived from nectar produced by plants of the genus Leptospermum, Kunzea and Knightia and combinations thereof.
  • the Leptospermum genus plants may be those in the myrtle family Myrtaceae and may include: Leptospermum scoparium, Leptospermum polygalifolium, Leptospermum sub pneumonia, Leptospermum semibaccatum, leptospermum trinervium, Leptospermum whitei, Leptospermum speciosum and Leptospermum liversidgei.
  • the Kunzea genus plants may be those of the species Kunzea ericoides or kanuka tree.
  • the Knightea genus plants may be those of the species Knightia excelsa or rewarewa tree.
  • a therapeutically effective amount of honey extract in the manufacture of a cosmetic product to inhibit MMP activity on or in the skin of a subject to whom the cosmetic product is applied, wherein the cosmetic skin care product contains a honey extract, the honey extract having a phenolic compounds to saccharides ratio of at least 5 times greater than the raw honey from which the extract is derived and including a mixture of at least ethanol, water and one or more MMP inhibitory phenolic compounds.
  • a method of treatment of a cosmetic skin condition by topical application of a cosmetic skin care product to the skin of a subject wherein the cosmetic skin care product acts to inhibit skin MMP activity and wherein the cosmetic skin care product contains a therapeutically effective amount of a honey extract, the honey extract having a phenolic compounds to saccharides ratio of at least 5 times greater than the raw honey from which the extract is derived and including a mixture of at least ethanol, water and one or more MMP inhibitory phenolic compounds.
  • the product may be used to cosmetically slow the visible signs of aging skin.
  • MMP's are activated by ultra violet radiation (UV) and, as noted above, over expression of MMPs can lead to a break down of collagen in the skin leading to reduced skin elasticity and formation of wrinkles.
  • the above method and use may be to increase skin elasticity, reduce photo aging of the skin and even influence skin wrinkles by reducing the length, depth and formation of wrinkles.
  • the cosmetic skin care product used may be applied once or twice daily depending on the final concentration and strength of the inhibitory compounds in the final product.
  • a method of producing an MMP inhibiting honey extract including the steps of:
  • the ratio of honey to ethanol in step (a) may be approximately 1 to 10 parts honey to 10 to 1 part ethanol.
  • the ratio may be approximately 1 part honey to 0.1, or 0.2, or 0.3, or 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1.0, or 1, or 1.5, or 2.0, or 2.5, or 3.0, or 3.5, or 4.0, or 4.5, or 5, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8.0, or 8.5, or 9.0, or 9.5, or 10 parts ethanol on weight basis.
  • the ratio may be approximately one part honey to one part ethanol or a 50:50 ratio by weight.
  • Mixing in step (a) may occur at a temperature of approximately 15, or 20, or 25, 30, or 35, or 40, or 45, or 50°C. In one embodiment, the temperature may be from 30 to 35°C. Mixing may occur in an agitated tank although other methods may be used. Lower temperatures (below 50°C) are preferable so as to avoid unwanted degradation in activity of actives present in the extract. Higher temperatures also create handling issues with ethanol becoming highly volatile. Mixing may occur for at least 1 minute. Mixing may occur for 10 to 120 minutes. In one embodiment, mixing occurs until a uniform puree is formed.
  • the mixture may be allowed to settle into the two phases noted in step (b).
  • Settling may for example involve stopping any agitation occurring and allowing the two phases to part via gravity. Settling may be encouraged by cooling the mixed solution, for example by passing coolant around the walls of the mixing tank. Settling may occur for at least 1 minute. In one embodiment, settling may take approximately 6 to 48 hours. In a further embodiment settling may take 1 to 2 weeks. As should be appreciated, there is no upper limit for this time period since the phenolic compounds post mixing are stabilised in the ethanol and separation can occur when processing constraints require further processing.
  • step (b) Separation in step (b) may occur by decanting one phase from the other.
  • the saccharides removed may primarily be fructose and sucrose.
  • the separated first saccharide or syrup phase may be recycled back into the first mixing step to recover further phenolics as desired noting that an optimum will be reached over time defining the limit of recycling being the point which the energy cost of recycling outweighs the potential extra gains in extracting the phenolics.
  • the ethanol concentration post decanting is approximately 70, or 75, or 80, or 85, or 90, or 95% (w/w). Some water ( ⁇ 18%) will also be present, the water being derived from what is present in the honey naturally.
  • Separation in step (c) may be via evaporation although other separation methods may be used such as via distillation.
  • One evaporation means may be via use of a falling film evaporator and evaporation under vacuum.
  • a vacuum in particular may be beneficial to avoid the need to elevate the temperature since higher temperatures may have an impact on the activity of the extracted phenolic compounds. As noted above, keeping the temperature lower is advantageous both to prevent potential harm to the active phenolic compounds and also to avoid ethanol handling issues. It is anticipated that some water may also be removed during the evaporation process.
  • Standardising steps may for example including blending of various extracts together to form a consistent amount of marker phenolic compound such as methyl syringate.
  • marker phenolic compound such as methyl syringate.
  • honey being a so called natural product can produce varying concentrations of phenolic compound depending on many factors such as floral origin, geographical origin and floral purity. Blending may be a way to achieve a consistent extract activity for further use in products such as cosmetic skin care products.
  • the final extract may be packaged prior to further processing.
  • Packaging may be useful for handling and storage. Packaging may also be important to ensure storage stability.
  • the extract may have a specific gravity below that of water.
  • the specific gravity may be approximately 0.9 to 0.999.
  • the specific gravity might be approximately 0.990.
  • the extract may be acidic.
  • the pH may be from approximately 3.0 to 6.0.
  • the pH may be approximately 4.0 to 5.0.
  • the extract may have a solids content post extraction of approximately 0.1% to 99.9% w/w, or up to as high as the extraction process will allow.
  • the solids content may be approximately 30 to 40% w/w.
  • the solids content may be 50 to 60% w/w.
  • the solids content may be 60 to 75%.
  • the solids content may be 75 to 85%.
  • Solids may be residual sugars, bee proteins, wax particles and environmental dust, all being typical solids found in honey. As should be appreciated, honeys finely filtered before under going the above extraction process may have fewer solids while unfiltered honeys may have solids at the higher end of the range noted.
  • the extract may be further characterised by having a honey aromatic odour and a golden yellow colour.
  • the extract may have a shelf life of at least 24 months provided it is stored in a cool and dry area and shielded from UV light.
  • honey also contains flavonoid compounds and it is the inventor's understanding the flavonoid compounds may also be present in the extract and skin care product.
  • the above extract, product, uses and methods allow the ability to include a far greater concentration of MMP inhibiting compounds in cosmetic skin care products than is possible with pure honey.
  • pure honey when used in skin care products confers unwanted characteristics to the product.
  • the extraction product and method also have some additional advantages namely, stabilisation and preservation of the phenolics and transdermal enhancing features. The result is an enhanced value product with better efficacy in combination with improved stability, handling and use properties.
  • honey is selected and mixed with ethanol in item 1 termed 'mix'.
  • the honey may be a honey known to have greater concentrations of phenolic and flavonoid compounds such as those derived from the genus Leptospermum, Kunzea and Knightia.
  • the ethanol may be 95% pure (absolute ethanol).
  • the honey and ethanol may be added at a 50:50 rate i.e. at equal weights, until the desired volume is reached.
  • the mixing process may be completed in an insulated tank at a temperature of 30-35°C for 30 to 60 minutes or until a smooth puree is formed.
  • Post mixing (item 1) and settling (item 2) the result is two phases of solution, the upper layer being a syrup formed primarily from the saccharides from the honey such as fructose and sucrose.
  • the lower layer is a mixture of ethanol, water extracted from the honey (typically 0-18%), and the phenolic compounds. Settling and separation may be enhanced by cooling the mixture for example via coolant pumped around the tank walls. Settling may take approximately 24 hours although this time period is variable depending on operator preference. Whilst in this state, the phenolic compounds are stable.
  • the upper saccharide rich layer is decanted off to leave the ethanol mixture.
  • the separated saccharide portion may be recycled (item 7) back into mixing (item 1) to maximise separation of the phenolics.
  • evaporation the phenolics are concentrated by removing ethanol and/or water via an evaporation process.
  • One evaporator processing unit may be a falling film evaporator. Evaporation may be completed under vacuum conditions in order to minimise the use of heat and possible damage to active compounds. Other separation methods may be used such as distillation.
  • Blending in item 5 refers to steps that might be completed to ensure a consistent or standardised product quality is achieved - for example blending of the product with other extracts to achieve a consistent and measurable level of phenolics in the final extract.
  • Item 6, packing may be complete for ease of handing and storage as well as to stabilise the extract during storage.
  • Table 1 A known honey extract composition and anticipated ranges for the various characteristics of the composition is illustrated in Table 1 below.
  • Table 1 Honey Extract Extract Characteristic Formulation 1 Envisaged Formulation Characteristic Ranges Odour Honey, aromatic Honey, aromatic Colour Golden yellow Golden yellow Ethanol Concentration 64% 50 to 80 % (v/v) Water Concentration 10% 5 to 40 % Specific Gravity/20°C (g/ml) 0.990 pH 4.60 4 to 5 Total Solids 34.9% 20 to 85 % Methyl Syringate concentration ( ⁇ g/mL) 200-1000 200 to 1000
  • honey extract was tested in skin care formulation base creams and rinses. Given the extract contains at least 15 fold higher concentration phenolic compounds than the raw honey, a relatively low concentration of honey extract, for example 1-4% (w/w) concentration equates to an equivalent honey concentration of 15-100% (w/w) in the skin care formulation.
  • Table 2- Example Cosmetic Skin Care Formulations Compound Cosmetic Product Day Moisturiser Night Moisturiser Facial Serum Hydrating Facial Mask Water 50-70% 60-70% 50-60% 50-70% Emollients 10-15% 15-20% - 15-20% Emulsifier 4-6% 6-7% - 4-6% Stabiliser 1-2% 1-3% 2-4% 1-3% Honey Extract 1-2% 1-2% 4-6% 2-4% Other active ingredients (not honey extract related) - - 10-15% -
  • each product may also contain preservatives and/or fragrance.
  • honey concentration would be entirely unworkable and sticky and of no commercial value.
  • Cosmetic skin care products containing the honey extract are by contrast are very easy to formulate and provide a far higher MMP inhibition rate over that of existing products.
  • An added advantage is that the residual ethanol in the extract assist in keeping the phenolics stable and minimises microbial growth when stored prior to formulation with the extra skin care compounds.
  • Ethanol may also act as a penetration enhancer assisting transfer of the phenolics into the skin. No unpleasant odour resulted from use of the extract as can be the case with honey.
  • MMP inhibitory effects of various honey extracts are illustrated in an in vitro experiment.
  • the MMP inhibitory effects of the extracts were tested directly.
  • Assays were prepared for MMP-1, MMP-2 and MMP-9 and treated with extracts made by the method above from manuka honey, kanuka honey, a blend of manuka and kanuka honey and clover honey. Multiple concentrations of honey extract were used.
  • FIGS 3 and 4 illustrate the inhibitory effects of the honeys against MMP-2 and MMP-9 respectively.
  • honey extracts showed MMP-2 inhibition to some degree with the clover honey extract having the least effect.
  • the normalised inhibitions based on 0.5% phenolics were manuka 69.5%; kanuka 24.0%, manuka/kanuka blend 76.0% and clover honey extract 8.5%.
  • MMP-9 inhibition were considerably higher than that from MMP-1 and MMP-2 inhibition.
  • MMP-9 inhibition with the phenolic rich honeys have well correlated normalised results and inhibitions (for a 0.5% phenolic concentration, the results were manuka honey extract 39.5% inhibition; kanuka honey extract 13.0% inhibition; manuka/kanuka blend 82.0% inhibition and clover honey 9.0% inhibition.
  • the MMP-1 inhibitory effects of differing concentrations were tested. After ethanol extraction, ethanol and some water were evaporated to obtain differing solids concentrations. The solids are mainly made up of sugars derived from the extracted honey. The samples were 20, 25, 45, 67 and 75% solids in the course of the evaporation. As shown in Figure 5 , MMP-1 inhibition increases at higher concentrations. The samples were also analysed by HPLC to determine methyl syringate concentration, which were determined to be as follows.
  • the sample with 0 % solids was a control containing no honey extract: % Solids in Sample Methyl Syringate Concentration (microgram/mL) 0% 0 0% 0 0% 0 0% 0 20% 3 20% 3 20% 3 25% 2 25% 2 25% 2 45% 30 45% 30 45% 30 67% 259 67% 259 67% 259 75% 238

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Claims (16)

  1. Hautpflegeprodukt, das eine therapeutisch wirksame Menge eines Honigextrakts umfasst, wobei das Honigextrakt ein Verhältnis von Phenolverbindungen zu Sacchariden umfasst, das zumindest 5-mal größer als der Rohhonig ist, von dem das Honigextrakt abgeleitet ist, wobei das Honigextrakt auch ein MMP-hemmendes Phenolextrakt und eine Mischung aus zumindest Ethanol und Wasser umfasst, um Hautalterung wie z. B. Verlust der Hautelastizität und somit die Bildung von Falten und/oder die nicht therapeutische Lichtalterung der Haut zu hemmen, wobei das Honigextrakt eine Konzentration von Methylsyringat aufweist, die ungefähr 5- bis 20-mal höher als die Konzentration in dem Rohhonig ist, wobei der Honig, aus dem das Extrakt produziert wird, im Wesentlichen von einem Nektar abgeleitet ist, der von Pflanzen der Gattung Leptospermum, Kunzea oder Knightia oder Kombinationen davon produziert wird.
  2. Hautpflegeprodukt nach Anspruch 1, wobei das Honigextrakt zwischen 200 und 1000 µg/ml Methylsyringat enthält.
  3. Hautpflegeprodukt nach Anspruch 1 oder 2, wobei das Extrakt vor Formulierung in dem Hautpflegeprodukt 10 bis 80 % Ethanol und 0,1 bis 18 % Wasser enthält.
  4. Hautpflegeprodukt nach einem der obigen Ansprüche, wobei das Produkt 0,1 bis 20 % (Gew./Gew.) Honigextrakt enthält.
  5. Hautpflegeprodukt nach einem der obigen Ansprüche, wobei das Produkt für die topische Verabreichung als Cremes, Gele, Salben, Riegel, Lotionen oder Flüssigkeiten formuliert ist.
  6. Verwendung eines Honigextrakts bei der Herstellung eines Hautpflegeprodukts nach einem der obigen Ansprüche zur Anwendung auf oder in der Haut eines Individuums, bei dem das Produkt angewandt wird, um Hautalterung wie z. B. den Verlust von Hautelastizität und somit die Bildung von Falten und/oder die nicht therapeutische Lichtalterung der Haut zu hemmen, wobei der Honig, aus dem das Extrakt produziert wird, im Wesentlichen von einem Nektar abgeleitet ist, der von Pflanzen der Gattung Leptospermum, Kunzea oder Knightia oder Kombinationen davon produziert wird.
  7. Verfahren zum Behandeln eines Hautleidens durch topische Anwendung eines Hautpflegeprodukts nach einem der Ansprüche 1 bis 5.
  8. Verfahren zum Produzieren eines Hautpflegeprodukts nach einem der Ansprüche 1 bis 5, das eine therapeutisch wirksame Menge eines Honigextrakts umfasst, das Phenolverbindungen umfasst, umfassend ein MMP-hemmendes Honigextrakt, wobei das Verfahren die Schritte beinhaltet:
    (a) Mischen eines ausgewählten Honigs mit Ethanol;
    (b) Trennen der Mischung, um eine saccharidkonzentrierte erste Phase aus einer zweiten Phase, die Ethanol, Wasser und eine oder mehrere MMP-hemmende Phenolverbindungen enthält, im Wesentlichen zu entfernen;
    (c) Durchführen eines weiteren Trennschritts, um die Konzentration von Phenolverbindungen zu erhöhen, durch Verringern der Ethanol- und/oder Wasserkonzentration;
    (d) Sammeln des entstehenden Phenolverbindungskonzentrats,
    wobei das Phenolverbindungskonzentrat 200 bis 1000 µg/ml Methylsyringat beinhaltet, und
    wobei der Honig im Wesentlichen von einem Nektar abgeleitet ist, der von Pflanzen der Gattung Leptospermum, Kunzea oder Knightia oder Kombinationen davon produziert wird.
  9. Verfahren nach Anspruch 8, wobei der Honig in Schritt (a) mit Ethanol in einem Verhältnis von 1 Gewichtsteil Honig zu 0,1 bis 10 Gewichtsteilen Ethanol vermischt wird.
  10. Verfahren nach Anspruch 8 oder Anspruch 9, wobei das Mischen in Schritt (a) bei einer Temperatur von 15 °C bis 50 °C erfolgt.
  11. Verfahren nach einem der Ansprüche 8 bis 10, wobei die Mischung gekühlt wird und sich setzen darf, bevor das Trennen in Schritt (b) beginnt.
  12. Verfahren nach einem der Ansprüche 8 bis 11, wobei das Trennen in Schritt (b) durch Dekantieren erfolgt.
  13. Verfahren nach einem der Ansprüche 8 bis 12, wobei das Trennen in Schritt (c) durch Verdampfen unter Vakuum erfolgt.
  14. Verfahren nach einem der Ansprüche 8 bis 13, wobei das Phenolkonzentrat 10 bis 80 % Ethanol und 0,1 bis 18 % Wasser beinhaltet.
  15. Kosmetische Zusammensetzung, die ein Honigextrakt umfasst, das mit dem Verfahren nach einem der Ansprüche 8 bis 14 produziert wurde.
  16. Hautpflegeprodukt, das eine therapeutisch wirksame Menge eines Honigextrakts umfasst, wobei das Honigextrakt ein Verhältnis von Phenolverbindungen zu Sacchariden umfasst, das zumindest 5-mal größer als der Rohhonig ist, von dem das Honigextrakt abgeleitet ist, wobei das Honigextrakt auch ein MMP-hemmendes Phenolextrakt und eine Mischung aus zumindest Ethanol und Wasser umfasst, zur Verwendung bei der Behandlung der extrinsischen Lichtalterung der Haut, wobei das Honigextrakt eine Konzentration von Methylsyringat aufweist, die ungefähr 5- bis 20-mal höher als die Konzentration in dem Rohhonig ist, wobei der Honig, aus dem das Extrakt produziert wird, im Wesentlichen von einem Nektar abgeleitet ist, der von Pflanzen der Gattung Leptospermum, Kunzea oder Knightia oder Kombinationen davon produziert wird.
EP15789343.9A 2014-05-06 2015-05-05 Matrix-metalloproteinasehemmender extrakt und verwendungsverfahren dafür Active EP3139938B1 (de)

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JP2003093488A (ja) * 2001-09-27 2003-04-02 Nagase & Co Ltd 消臭組成物および消臭方法
JP2005139070A (ja) * 2003-11-04 2005-06-02 Kanebo Cosmetics Inc 皮膚化粧料
KR20050048287A (ko) * 2003-11-19 2005-05-24 주식회사 쟌퀼 아토피성 피부염을 개선을 위한 화장품 조성물
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US11273121B2 (en) 2022-03-15
CN106659744A (zh) 2017-05-10
US20170071849A1 (en) 2017-03-16
EP3139938A1 (de) 2017-03-15
CN106659744B (zh) 2020-12-08
CN112826785A (zh) 2021-05-25
WO2015170993A1 (en) 2015-11-12
NZ624517A (en) 2015-10-30
CN112826785B (zh) 2023-08-01

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